The present invention relates to crystal forms of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide having hypoglycemic activity or a PDE5 inhibitory effect, and a method for manufacturing the same.
When a compound containing crystal polymorphs is used as a medicine, it is often necessary to produce a drug substance having a specific crystal form to guarantee the consistency of physicochemical and biological properties of the compound. Futhermore, in the process of manufacturing a drug substance, it is often important to separate out a particular form of crystal during the crystallization procedure, in order to maintain defined levels of the yield and purification efficiency.
3-(2,4-Dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide has been disclosed as a benzimidazole compound having hypoglycemic activity or PDE5 inhibitory effect in WO97/24334 (cf. Example 251). However, the existence of crystal polymorphs of this compound has not hitherto been recognized, nor has a substantially and crystallographically pure crystal of this compound having a particular form been obtained.
It is an object of this invention to provide a substantially and crystallographically pure crystal form of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide that is useful as a medicine, a method for manufacturing the same, and a medical composition comprising the same.
The present inventors studied various conditions for crystallizing 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide. As a result, they found three forms of crystals in this compound. Herein, these three crystal forms are referred to as crystal forms A, B and C. The inventors also discovered that crystal forms A and B have advantages over other crystal forms, respectively. That is, crystal form A is crystallographically more stable than crystal form B and C, though it forms smaller crystals. It is thus more easily obtainable as substantially and crystallographically pure crystals, which is favorable for maintaining the quality of a pharmaceutical preparation as a medicine. On the other hand, crystal form B, while not as crystallographically stable as crystal form A, forms larger crystals than crystal form A, so that it can be isolated with greater ease, by filtration, and efficiently purified, by crystallization.
Furthermore, the present inventors found that each crystal form can be obtained in a substantially pure crystallographic form and in an industrially stable manner, by using a crystallization method preferable for the respective form, thereby accomplishing the present invention.
Thus, this invention relates to
(1) a substantially and crystallographically pure crystal form of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide having the following X-ray powder diffraction values (2xcex8), with an error range of xc2x10.2, in an X-ray powder diffraction assay using CuKxcex1-ray as a characteristic X-ray:
Angle 2xcex8(xc2x0): about 4.7, about 9.5, about 10.5, about 15.6, and about 18.4; and
(2) a substantially and crystallographically pure crystal form of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide having the following X-ray powder diffraction values (2xcex8), with an error range of xc2x10.2, in an X-ray powder diffraction assay using CuKxcex1-ray as a characteristic X-ray:
Angle 2xcex8(xc2x0): about 4.4, about 8.9, and about 13.4.
The present invention also relates to a pharmaceutical composition comprising crystal form of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide described in (1) as an active ingredient. The present invention also relates to a pharmaceutical composition comprising crystal form of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentyl-sulfonyl)-3H-benzimidazole-5-carboxamide described in (2) as an active ingredient.
The present invention further relates to a process for producing crystal form (1) above, which comprises crystallization of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide from an organic solvent or a mixture of an organic solvent and water. The present invention also relates to a process for producing crystal form (2) above, which comprises crystallization of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide by adding acid to the solution of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide dissolved in an organic solvent or a mixture of an organic solvent and water in the presence of alkali.
As used herein, the term xe2x80x9csubstantially and crystallographically purexe2x80x9d means that other crystal forms are not analytically identifiable. In this context, analysis refers to at least one of powder X-ray diffraction, infrared spectrophotometry (IR) and thermogravimetry/differential thermal analysis (TG/DTA), which are described below.
Crystal form A of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide (often referred to as Compound (I) hereafter) is characterized as having the following X-ray powder diffraction values (2xcex8), with an error range of xc2x10.2, in an X-ray powder diffraction assay using CuKxcex1-ray as the characteristic X-ray:
Angle 2xcex8(xc2x0): about 4.7, about 9.5, about 10.5, about 15.6, and about 18.4.
More specifically, for example, crystal form A shows the following diffraction values.
Crystal form B of Compound (I) is characterized as having the following X-ray powder diffraction values (2xcex8), with an error range of xc2x10.2, in an X-ray powder diffraction assay using Cukxcex1-ray as a characteristic X-ray:
Angle 2xcex8(xc2x0): about 4.4, about 8.9, and about 13.4.
More specifically, for example, crystal form B shows the following diffraction values.
Furthermore, crystal form C of Compound (I) has the following X-ray powder diffraction values (2xcex8), with an error range of xc2x10.2, in an X-ray powder diffraction assay using CuKxcex1-ray as a characteristic X-ray:
The X-ray powder diffraction values (2xcex8) described above were determined using the following apparatus and conditions:
Apparatus: Rigaku RINT-1500 (Rigaku Denki Kogyo Inc.);
Characteristic X-ray: CuKxcex1 rays (using a monochrometer);
Tube electric current/tube voltage: 40 kV/30 mA;
Detector: proportional counter;
Scanning speed: 2xcex8=3xc2x0-40xc2x0; and
Slit system: divergence slit, 1xc2x0; scattering slit, 1xc2x0; receiving slit 0.3 mm.
Crystal forms A, B and C of Compound (I) can also be discriminated by IR spectra. The significantly different peaks in the absorption pattern for each crystal form in IR (KBr) spectra,determined by infrared spectrophotometric analysis (KBr disk method), are contrasted in the following table:
The IR spectra shown above were obtained using the following apparatus and conditions described below.
Apparatus: PERKIN ELMER 1650 FT-IR (Perkin-Elmer, Japan);
Measuring method: KBr-disk method; and
Disk: 3 mm in diameter.
IR data for each crystal form, determined by Nujol method, as well as for Compound (I), generated and purified according to a conventional method (WO97/24334), are shown in the following table:
In addition, crystal forms A, B and C of Compound (I) can also be distinguished by thermogravimetry/differential thermal analysis (TG/DTA) as described below:
Crystal form A: a maximum melting endotherm at the extrapolation initiation temperature of about 211xc2x0 C.;
Crystal form B: a maximum transient endotherm at the extrapolation initiation temperature of about 186xc2x0 C. and a maximum melting endotherm at the extrapolation initiation temperature of about 211xc2x0 C.; and Crystal form C: a maximum melting endotherm at the extrapolation initiation temperature of about 102xc2x0 C. and a subsequent maximum exotherm, a maximum melting endotherm at the extrapolation initiation temperature of about 211xc2x0 C., and a 1-2% weight loss around the former maximum melting endotherm.
The aforesaid thermogravimetry/differential thermal analysis (TG/DTA) was determined with the apparatus and under the conditions as described below:
Apparatus: SII TG/DTA 6300 (Seiko Instruments Inc.);
Temperature condition: 30xc2x0 C. (0 min)xe2x86x9210xc2x0 C./minxe2x86x92350xc2x0 C.;
Sample container: Al sealed container;
Atmosphere: N2, 300 ml/min; and
Sampling time: 0.5 s.
A substantially and crystallographically pure crystal form A of Compound (I) can be manufactured in a stable manner by dissolving compound (I) in an organic solvent or a mixture of organic solvent and water, heating the solution, and then by putting this solution into crystallization during heating. For the solvent, a mixture of water and an organic solvent, including, but not limited to, amides (e.g. N,N-dimethylformamide, N,N-dimethylacetamide, etc.), alcohols (e.g. methanol, ethanol, 1-propanol, 2-propanol, etc.) and ketones (e.g. acetone, methylethyl ketone, etc.), is preferably used. One or more of these solvents can be combined in the mixed solvent. Among aqueous/organic solvent mixtures, a mixed solvent of a ketone and water is more preferred, and a mixed solvent of acetone and water is even more preferred.
Since solubility varies with the type and composition of solvent used, there is no particular limitation on the mixing rate of an organic solvent and water. When dissolving compound (I), a higher ratio of organic solvent to water has the advantage of giving improved solubility; the organic solvent to water ratio is preferably, from 100:0 to 50:50 (w/w), and more preferably, from 100:0 to 70:30 (w/w). When completing crystallization of compound (I), it is advantageous to reduce the ratio of the organic solvent in a relative manner in order to obtain a sufficient yield; the organic solvent to water ratio is preferably reduced to 95:5 to 5:95 (w/w), and more preferably to 90:10 to 30:70 (w/w).
To precipitate the crystals during heating, a poor solvent, such as water, is added to the solution of compound (I) in the aforesaid solvent during heating; alternatively, the organic solvent is evaporated. In addition, if compound (I) is maintained at high temperature, it is possible to precipitate the crystals by cooling.
In any method as described above, to obtain crystal form A, it is desirable to initiate the crystallization at 30xc2x0 C. or higher. There is no defined upper limit of the initiation temperature since the solubility varies with type or composition of solvent used. The initiation temperature may be between 30xc2x0 C. and the boiling point of the solvent employed, and below the solubility of crystal form A. Preferably, the crystallization is initiated at the temperature higher than 40xc2x0 C. to more stably obtain crystal form A. In the context of the present invention, xe2x80x9cinitiation of crystallizationxe2x80x9d refers to the time any crystals start to be precipitated, if no seed crystals are added, or to the time any crystals other than seed crystals start to be precipitated if seed crystals are added.
Crystal form A of compound (I) can also be manufactured by maintaining a suspension containing compound (I), in any crystalline form or in amorphous form or a mixture thereof, in a solvent in the heat so as to induce the transition of crystal form in the suspended state.
In this instance, the heating temperature is not limited to a certain range, so long as it ensures the transition; however, it is desirable to retain a temperature of 30xc2x0 C. or higher in order to obtain crystal form A in a stable manner. Again, there is no defined upper limit on the retention temperature since the solubility varies with the type or composition of solvent used. The retention temperature may be between 30xc2x0 C. and the boiling point of the solvent employed, and also below the solubility of crystal form A. A retention temperature of 40xc2x0 C. or higher is preferable to obtain crystal form A in a more stable manner.
There is no particular limitation on the retention time so long as it can ensure the transition; however, it is preferably at least five minutes, more preferably at least one hour. There is no defined upper limit on the retention time; however, from the economic point of view, it is preferably three days or less, more preferably one day or less.
Furthermore, it is also possible to combine the crystallization and transition methods above, although either can be employed singly, to obtain crystal form A. To reduce the possibility of crystallization of crystal forms other than desired crystal form of Compound (I) in these crystallization and transition methods, it may be effective to add a small amount of seed crystals of form A to the solution, for example, prior to the initiation of crystallization.
In order to increase the yield, crystals can be grown using seed crystals of form A already crystallized by further adding a poor solvent, such as water, or by cooling the solution after crystals have come out. After crystallization, the filtrate is removed by a conventional method, for example, centrifugation, filtration, and such, and the crystals are dried by a conventional drying method, such as vacuum drying or hot air drying, and such, to obtain the desirable crystal form A.
A substantially and crystallographically pure crystal form B of Compound (I) can be stably manufactured through crystallization of free Compound (I), by adding an acid to a salt solution of Compound (I) and a base.
The bases to form a salt with Compound (I) include, but are not limited to, inorganic bases (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, etc.), and organic bases (e.g. 4-N,N-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]-7-undecene, 1,5-diazabicyclo[4.3.0]-5-nonene, triethylamine, imidazole, etc.). These bases can be used alone or in combination, as a mixture.
It is not necessary to isolate the salt form of Compound (I) with a base beforehand. A salt solution of Compound (I) and a base can be prepared by adding base in an amount sufficient to dissolve the suspension of free Compound (I) in the solvent system used for crystallization, or by utilizing the base used in the condensation reaction as the base to form the salt form of Compound (I).
There is no limitation on the amount of the base so long as it is sufficient to dissolve Compound (I) completely in the solvent used for Compound (I) in the presence of the base. However, in general, the total amount of the base used is preferably half to 10-fold of the equivalent amount of Compound (I). More preferably, an equivalent amount to a 4-fold amount of base is used.
Acids to be used for neutralization include, but are not limited to, inorganic acids (e.g. hydrochloric acid, sulfuric acid, phosphoric acid, etc.) and organic acids (e.g. acetic acid, propionic acid, methane sulfonic acid, etc.) can be used. These acids can be used alone or in combination, as a mixture.
There is no limitation on the amount of the acid, so long as it is sufficient to generate free Compound (I), by neutralizing the base used for dissolution of compound (I), thereby precipitating crystal form B. Typically, the total amount of the acid applied is preferably 0.1- to 10-fold, and more preferably 0.2- to 2-fold the amount of the base used for dissolution of Compound (I).
There is no particular limitation on the types of solvents used for dissolution; organic solvents, water, or mixtures thereof may be used. There is no particular limitation on the types of organic solvents; however, from the perspective of solubility and operationality, they are exemplified by amides (e.g. N,N-dimethylformamide, N,N-dimethyl-acetamide, etc.), alcohols (e.g. methanol, ethanol, 1-propanol, 2-propanol, etc.) and ketones (e.g. acetone, methyl ethyl ketone, etc.). These solvents may be used singly or in combination, at any mixing ratios. For organic solvents, alcohols are preferable, and methanol is particularly preferable. In addition, in the case where an inorganic base or acid is used, it is preferable to include water as the solvent in order to remove salts generated.
To ensure crystallization and yield of crystal form B of Compound (I) in the crystallization process, a small amount of seed crystals of form B can be added to the solution.
Typically, the crystallization temperature is below the boiling point of the solvent used; however, the crystallization temperature varies with the solvent system used and the dissolubility thereof and, thus, is not specifically defined. However, this temperature is required to be within the range that can prevent transition to crystal form A of Compound (I) once crystal form B is crystallized.
When Compound (I) is dissolved in the presence of a base, and subsequently an acid is added to precipitate crystal form B, this form would exist as a relatively stable form even if it were suspended in a solvent. However, transition to crystal form A occurs if the temperature becomes too high or the retention time is extended for too long. Thus, it is necessary to prevent this transition in order to obtain crystal form B. The temperatures at which crystal form B transitions into crystal form A, and the retention times required to complete isolation will vary depending on the types and composition used for the process, as well as on the interaction between the temperature and retention time. Therefore, the temperature and retention time are not specifically defined. However, lower temperatures and shorter retention times are favorable. Typically, the retention temperature is preferably below the boiling point of the solvent, or 60xc2x0 C. or below, and more preferably 55xc2x0 C. or below. Also, typically, the retention time until completion of the isolation is preferably 5 days or less, and more preferably 2 days or less at the temperature of, for example, 50xc2x0 C.
After crystallization, the filtrate is removed by a conventional method, for example, centrifugation, filtration, and such, and the crystals are dried by a conventional drying method such as vacuum drying, hot air drying, and such, to obtain the desirable crystal form B.
In addition, the present invention provides a pharmaceutical composition comprising the crystal form A of Compound (I), obtained as described above, as an active ingredient.
Compound (I) can be used for prevention or therapy of various diseases, on the basis of its hypoglycemic activity or PDE5 inhibitory effect. It is useful for treatment or prevention of diseases including, but not limited to, polycystic ovary syndrome, gestational diabetes, diabetic complications (diabetic osteopenia, osteoporosis), autoimmune diseases, pancreatitis, cachexia (progressive weight loss due to lipolysis, myolysis, anemia, edema, anorexia and the like) and in chronic diseases such as cancer, tuberculosis, endocrine diseases, and AIDS).
The pharmaceutical composition of the present invention may be prepared by mixing crystal form A of Compound (I) with a pharmaceutically acceptable carrier, such as an organic and inorganic vehicle, in a solid, semi-solid or liquid state suitable for oral, parenteral administration and external application (local application). The pharmaceutical composition may be in a solid form, such as tablet, granule, powder, capsule, dragee and suppository; in a liquid form, such as suspension, milky lotion, syrup, emulsion, lemonade, lotion, etc.; ointment; and gel. The above preparation may contain, if necessary, an auxiliary, stabilizer, wetting agent, emulsifier, buffer, and an ordinary additive, such as lactose, citrate, tartarate, stearate, magnesium stearate, clay, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao oil, ethylene glycol, etc.
The dose of Compound (I) can be routinely determined, depending on the age and conditions of the patient, and the type and state of the disease. Typically, 1 to 100 mg/kg of compound (I) for oral administration, and 0.1 to 10 mg/kg for intramuscular or intravenous injection, administered one to four times a day.